Histidine-rich glycoprotein (HRGP), a plasma protein with antiheparin and antifibrinolytic activity, has been associated with thrombophilia in three families. Therefore, it may promote hypercoagulability. The following objectives have been achieved in the laboratory: purification of the HRGP, using a combination of cobalt-sepharose, and development of an enzyme-linked immunosorbent assay for its quantitation. We have confirmed HRGP's antiheparin activity.In addition, we have demonstrated that HRGP binds to activated human platelets. The amount of binding is increased by several divalent cations, but not calcium or magnesium. It is also enhanced significantly by plasminogen, although HRGP does not have the reciprocal effect of increasing plasminogen binding to platelets. These observations suggest that platelet-bound plasminogen may serve as a binding site for HRGP, although there appear to be other sites as well.